SNFGE SNFGE
 
Thématique :
- MICI
Originalité :
Intermédiaire
Solidité :
Intermédiaire
Doit faire évoluer notre pratique :
Immédiatement
 
 
Nom du veilleur :
Professeur Philippe SEKSIK
Coup de coeur :
 
 
Gastroenterology
  2018/05  
 
  2018 May;154(6):1660-1671.  
  doi: 10.1053/j.gastro.2018.01.043  
 
  Pharmacokinetics and Exposure Response Relationships of Ustekinumab in Patients With Crohn's Disease  
 
  Adedokun OJ, Xu Z, Gasink C, Jacobstein D, Szapary P, Johanns J, Gao LL, Davis HM, Hanauer SB, Feagan BG, Ghosh S, Sandborn WJ  
  https://www.ncbi.nlm.nih.gov/pubmed/29409871  
 
 

Abstract

BACKGROUND & AIMS:

Ustekinumab is a monoclonal antibody that binds with high affinity to the p40 subunit of human interleukin 12 (IL12 and IL23) that has been approved for treatment of patients with moderate to severe Crohn's disease (CD). However, there are few data on its pharmacokinetic properties or the relationship between drug exposure levels and patient response. We collected data from 2 Phase 3 induction studies and 1 maintenance study to determine ustekinumab's pharmacokinetic features, relationship between exposure and response, and optimal serum concentrations for efficacy.

METHODS:

We collected data on serum concentrations of ustekinumab and efficacy from induction studies of patients with moderate to severe CD given ustekinumab for 8 weeks following a single intravenous dose (either 130 mg or approximately 6 mg/kg). We collected the same data from a maintenance study of patients with a response to ustekinumab in the induction study who then received subcutaneous injections (90 mg) every 8 or 12 weeks for 44 weeks. At week 44 of the maintenance study (52 weeks after treatment began), patients were evaluated for the primary endpoint of clinical remission (defined as a CD activity index score below 150 points), endoscopic markers of efficacy, and serum level of C-reactive protein. Ustekinumab concentration data were categorized into quartiles and relationships between exposure and response were assessed. Optimal concentration cutoff values were evaluated using receiver operating characteristic curve analysis.

RESULTS:

Serum concentrations of ustekinumab over time were proportional to dose and did not differ significantly between the induction studies. In the maintenance study, ustekinumab concentration reached the steady state by the second maintenance dose; the median trough concentration was approximately threefold higher in patients given ustekinumab at 8-week intervals compared with 12-week intervals. Ustekinumab serum concentrations associated with rates of clinical remission and endoscopic efficacy endpoints, correlated inversely with level of C-reactive protein, and did not associate with use of immunomodulators. Trough concentrations of ustekinumab of 0.8 (or even up to 1.4 μg/mL) or greater were associated with maintenance of clinical remission in a higher proportion of patients than patients with lower trough concentrations.

CONCLUSIONS:

In an analysis of data from Phase 3 studies of patients with moderate to severe CD, we found serum concentrations of ustekinumab to be proportional to dose and associate with treatment efficacy. Concentrations of ustekinumab did not seem to be affected by cotreatment with immunomodulators. Clinicaltrials.gov no. NCT01369329 (UNITI 1), NCT01369342 (UNITI 2), and NCT01369355 (IM-UNITI).

 

 
Question posée
 
Quelles sont les caractéristiques pharmacocinétiques de l'ustekinumab ?
 
Question posée
 
Les concentrations sériques d'ustekinumab semblent proportionnelles à la dose et à l'efficacité du traitement.
 
Commentaires

Ces données issues des essais de phase III mettent en évidence une relation linéaire entre le taux sérique et la dose sans influence apparemment d’un immunosuppresseur concomitant. Les données de phase 4 ou de ‘pratique clinique’ seront nécessaires pour valider ces premiers résultats.

 
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